Newer antibiotics have an advantage because they were developed to have activity against drug-resistant bacteria. However, activity against resistant bacteria per se cannot be demonstrated showing statistical significance because infections with resistant organisms are rare.
Since statistical superiority cannot be shown due to practical limitations, trial design using noninferiority (NI) margins and guidelines for conducting NI trials were established with tight NI margins of 10%.
The choice of comparator in the trials has also become quite important. The acceptable comparator is not necessarily an older member of the same class of antibiotic being tested, but rather an antibiotic that is the gold standard for the infection being tested.
In this new paradigm, a new antibiotic that is active against resistant bacteria but is somewhat less active in the Phase III study than the gold-standard antibiotic is not likely to be approved. As a result, a new antibiotic that could be useful to treat resistant bacteria when standard therapy fails may not be available.
Tight measurable endpoints are now required to show that a new antibiotic is NI to the best approved antibiotic. Early 48 to 72 hour endpoints are now selected as the primary end points, while later curative effects have become secondary.
There are two reasons for the selection of early indicators of activity: early endpoints dictate a shorter treatment duration, limiting patient exposure and lowering the probability of resistance selection; and due to the high potency of antibiotics that are now in development, trials using cure rates at the end of treatment do not differentiate them from each other.
However, measuring cures at early time points may be useful when comparing antibiotics within a class, but comparing bactericidal to bacteriostatic antibiotics could lead to misleading results, eliminating more effective antibiotics that have a later but more curative effect. This ultimately limits physician options and negatively impacts patient outcomes. In addition, antibiotics with anti-inflammatory activity may show more rapid clinical improvement but they may not necessarily be better antibiotics.
Antibiotic stewardship is becoming more common than in the past decades, resulting in more conservative antibiotic use as doctors “watch and wait” and limit empiric use to immunocompromised or critically ill patients in teaching hospitals. But in a busy general practitioner or pediatric setting, oral antibiotics are still frequently prescribed. Overuse can be harmful for many reasons including generating resistance, affecting bowel flora, and inducing allergic reactions.
For example, over 35% of pneumococci are resistant to macrolides, and the susceptibility of pneumococci to penicillins has decreased, requiring much higher doses than previously used. In addition, methicillin-resistant Staphylococcus aureus (MRSA) is now commonplace, and Gram-negative pathogens are increasingly resistant to current agents. It is essential that new community antibiotics be developed, but how can these antibiotics be proven safe enough for general use outside the hospital where a larger population is exposed?
The FDA’s intent is to approve antibiotics only for serious infections (e.g., ABSSSI, PORT 3-4 CABP) within the hospital setting. When proven safe and effective in a postmarketing environment, it may be possible to transition them to outpatient community use. However, it is unclear how an oral-only antibiotic can be approved, as they cannot be used for serious infections that most often require intravenous antibiotics. Oral-only antibiotics will face greater regulatory challenges and require more innovative clinical trial designs. New oral antibiotics may still get approved, but their development will be more challenging than in the past.